2/2 Brain, Behavior and Genetic Studies of the 22q11 Deletion Studies

描述（由申请人提供）：22 q11 DS的脑行为和遗传研究是费城儿童医院（CHOP）和宾夕法尼亚大学（Penn）之间的合作RO 1。这项合作结合了遗传学和神经生物学范式，以促进对精神分裂症（SCZ）发病机制的理解。CHOP已经建立了超过800例22 q11 DS患者的最大可用样本，这些患者已通过遗传学和基因组学进行了充分表征。患有22 q11 DS的青少年和年轻人（23-30%）发生SCZ的风险很大，疾病表现和病程与一般人群（1%）中的SCZ相似。Penn在SCZ的脑行为研究方面拥有丰富的经验，包括表型表征，计算机神经认知测试和提供互补定量表型的神经影像学测量。这项合作的目标是利用这个独特的22 q11 DS样本，获得大脑结构和功能的神经精神、神经认知和神经影像表型。该设计将包括使用基于体积的形态测量的磁共振成像（MRI）对大脑结构的年龄分层测量，以及与扩散张量成像（DTI）的连接。功能性磁共振成像（fMRI）研究将检查响应神经行为探针激活的大脑回路（具体目标1）。将22 q11 DS中的神经精神、神经行为和神经影像学表型与SCZ患者、具有SCZ临床和遗传风险的患者以及心脏和健康对照进行比较。需要这些小组来建立表型特征和定量脑行为测量及其相互作用的概况（具体目标2）。为了建立产生神经精神、神经行为和神经影像表型的遗传机制，将使用全基因组方法和选定的候选基因来检查与常见SNP的关联。将在整个基因组和22 q11 DS区域内的22 q11 DS样本中检测拷贝数变体（CNV）与SCZ定量表型的相关性。将对22 q11 DS区域的基因和缺失患者中选定的候选基因进行“非缺失”等位基因的下一代深度测序，以确定特定突变或等位基因是否与22 q11 DS个体中SCZ相关内表型的极端值相关（具体目标3）。标本将被送往NIMH储存库进行转化和DNA提取。将保持数据收集和质量控制，并将经验证的数据定期上传到NIMH储存库（具体目标4）。该项目将是第一个采取与SCZ相关的常见缺失并阐明其行为，神经生物学和遗传底物的项目。除了可能更好地了解22 q11 DS的严重表现外，这些结果还将有助于确定在一般人群中导致SCZ的途径，从而指出新的治疗方法。 公共卫生相关性：精神分裂症（SCZ）是一种复杂的大脑疾病与遗传基质。它经常出现在青春期和成年早期，具有破坏性影响。在22 q11 DS患者中，23-30%的人发展为SCZ表型，这为探索SCZ的发病机制提供了独特的机会。基因组学和神经生物学的整合是理解缺陷原因的关键，从而导致早期检测和推进新的治疗方法。

DESCRIPTION (provided by applicant): Brain-Behavior and Genetic Studies of the 22q11DS is a collaborative RO1 between Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania (Penn). The collaboration combines genetic and neurobiologic paradigms to advance understanding of the pathogenesis of schizophrenia (SCZ). CHOP has established the largest available sample of over 800 patients with 22q11DS who have been well characterized by genetics and genomics. There is a substantial risk for developing SCZ in adolescents and young adults with 22q11DS (23-30%), with illness presentation and course similar to SCZ in the general population (1%). Penn has extensive experience in brain-behavior studies in SCZ including phenotypic characterization, computerized neurocognitive testing, and neuroimaging measures that provide complementary quantitative phenotypes. The goal of the collaboration is to capitalize on this unique sample of 22q11DS and obtain neuropsychiatric, neurocognitive, and neuroimaging phenotypes of brain structure and function. The design will include age- stratified measures of brain structure with Magnetic Resonance Imaging (MRI) using volume-based morphometry, and connectivity with Diffusion Tensor Imaging (DTI). Functional MRI (fMRI) studies will examine brain circuitry activated in response to neurobehavioral probes (Specific Aim 1). The neuropsychiatric, neurobehavioral and neuroimaging phenotypes in 22q11DS will be compared to patients with SCZ, those at clinical and genetic risk for SCZ, and cardiac and healthy controls. These groups are needed to establish the profile of phenotypic features and quantitative brain-behavior measures and their interactions (Specific Aim 2). To establish genetic mechanisms producing the neuropsychiatric, neurobehavioral and neuroimaging phenotypes, association with common SNPs will be examined using a genome-wide approach and selected candidate genes. Associations of copy number variants (CNVs) with SCZ quantitative phenotypes will be tested in 22q11DS samples both across the genome and within the 22q11DS region. Deep next generation sequencing on the "non-deleted" allele will be performed for genes in the 22q11DS region and selected candidate genes in patients with the deletion to determine whether specific mutations or alleles are associated with extreme values of SCZ-related endophenotypes in 22q11DS individuals (Specific Aim 3). Specimens will be sent to the NIMH repository for transformation and DNA extraction. Data collection and quality control will be maintained and verified data will be regularly uploaded to the NIMH repository (Specific Aim 4). The proposed project will be the first of its kind to take a common deletion associated with SCZ and elucidate its behavioral, neurobiological and genetic substrates. Beyond the potential for yielding a better understanding of a severe manifestation of 22q11DS, the results will help identify pathways leading to SCZ in the general population in a way that will point to novel treatments. PUBLIC HEALTH RELEVANCE: Schizophrenia (SCZ) is a complex brain disorder with genetic substrates. It often emerges in adolescence and early adulthood with devastating effects. Of individuals with 22q11DS, 23-30% develops the SCZ phenotype, providing a unique opportunity to probe the pathogenesis of SCZ. Integration of genomics and neurobiology is key to understanding the causes of deficits, leading to early detection and advancing novel treatments.